Ibrutinib is an oral Bruton's tyrosine kinase (BTK) inhibitor for the treatment of mantle cell lymphoma, chronic lymphocytic leukemia, and Waldenström's macroglobulinemia. The chemical name of Ibrutinib is 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one. The structure of ibrutinib is shown below.

Synthesis of ibrutinib and intermediates thereof has been disclosed in U.S. Pat. No. 8,158,786, Honigberg et al., shown below as Scheme 1.

Honigberg et al. disclose a process for preparing ibrutinib by coupling compound 9 with compound 10 under Mitsunobu reaction conditions to obtain compound 7a, deprotecting compound 7a (i.e. removal of the Boc group) to form compound 8a, and acylating the nitrogen of the 3-piperidine moiety of compound 8a with acryloyl chloride using standard acylation conditions to form ibrutinib. According to this process, compound 9 is coupled with compound 10 in the presence of polymer-bound triphenylphosphine (TPP), and ibrutinib is formed by acylating compound 8a using organic solvent (dichloromethane, DCM) and organic base (triethylamine, NEt3). In order to isolate ibrutinib from the acylation reaction mixture, multiple extraction and wash steps are required.
U.S. Patent Publication No. 2014/0275126 A1, Pye et al., discloses a similar process for preparing ibrutinib shown in Scheme 2, below.

In this reaction scheme, compound 6 is formed by reacting compound 4, which is derived from a series of prior reactions, with a hydrazine derivative. The pyrimidine portion of compound 7 is prepared by reacting compound 6 with formamide. Similar to the disclosure of Honigberg et al., compound 8 is prepared by deprotecting compound 7, and ibrutinib is obtained by acylating the nitrogen of the 3-piperidine moiety of compound 8 with acryloyl chloride using standard acylation conditions to form ibrutinib. As in Honigberg et al., the isolation of ibrutinib from the acylation reaction mixture requires multiple extraction and wash steps.
In view of the foregoing, the need exists for an improved process to produce ibrutinib with commercially acceptable yields and increased efficiency.